Novel treatments for chronic pain with diminished risk of addiction have not been forthcoming despite much effort. Indeed there is increasing evidence that current treatment modalities themselves actually can exacerbate pain states. Recent studies in our laboratories and other laboratories suggest that new approaches are needed to deal with the changes in expressed genes that may underlie hyperalgesic actions, tolerance and negative reinforcement which may lead to drug seeking behavior. Thus there is a need for new kinds of treatment that require new approaches to drug design. To overcome these deficiencies and more fully understand new mechanisms that can explain why current methods for treating many chronic pain states (chronic inflammatory pain, neuropathic pain, visceral pain, etc.) are not successful, we will develop novel ligands based on new mechanistic insights that can overcome the undesirable actions of currently used opiates. Our specific aims for this Program Project are: 1) Effective administration of the financial, personnel and scientific aspects of a highly multidisciplinary group of scientists in several departments; 2) Operate an efficient and effective Synthesis Core to synthesize all the compounds needed in this project; 3) Provide a multifacited Biochemical Core to perform as necessary binding affinity, second messenger, tissue and animal assays to advance this research; 4) Design and synthesis of novel balanced mu/delta ligands that possess greatly reduced opioid toxicity and which show minimal or no tolerance; 5) Design and synthesis of novel dynorphin A non-opioid ligands that act at a putative novel binding site on bradykinin receptors; 6) Synthesize bivalent novel ligands that are mu/delta receptor agonists/bradykinin receptor antagonists that modulate pain; 7)Develop novel pharmacology and molecular biology methods to provide an understanding of the mechanism(s) of action of non-opioid dynorphin ligands that affect bradykinin receptors and modulate chronic pain by novel pathways; 8)Examine mechanisms of opioid induced neuroplasticity, opioid withdrawal and tolerance; 9)Determine changes occurring in the CNS which lead to enhanced spinal levels of non-opioid dynorphins which interact with the bradykinin receptor to produce hyperalgesia and mediate opioid withdrawal and contribute to negative reinforcement and dependence; 10) Determine the functional regulation of opioid receptors, especially as related to opioid induced tolerance/hypersensitivity. PUBLIC HEALTH RELEVANCE: There are still many unmet public health needs in the treatment of pain and drug abuse in our society and worldwide. In this research we will examine the design, synthesis, and biological evaluation of novel peptide and peptidomimetic ligands for the treatment of prolonged pain, especially neuropathic pain that will address new mechanisms of pain control with minimal side effects such as drug seeking behavior and tolerance.